Structural Insights into the TES/TFA Reduction of Differently Substituted Benzofurans: Dihydrobenzofurans or Bibenzyls?

Article abstract of DOI:10.1055/s-0040-1705949

Various polysubstituted benzofurans were reduced by using triethylsilane in trifluoracetic acid. 2,3-Dihydrobenzofurans or bibenzyl compounds were obtained in high yields, depending on the nature of the substituents at C2 and on the benzene ring of the co

Full text of DOI:10.1055/s-0040-1705949

SYNLETT
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 31, A–F
letter
A
en
R. D’Orsi et al.
Letter
Synlett
Structural Insights into the TES/TFA Reduction of Differently Sub-
stituted Benzofurans: Dihydrobenzofurans or Bibenzyls?
R2
Rosarita D’Orsi
Ilaria Caivano
Maria Funicello
Paolo Lupattelli
9 examples
R1 = alkyl, Ph, 4-ClC6H4, 4-F3COC6H4
R2 = H, R3 = EWG
R3
R1
reduction of
R2
a
O
0
0
0
0
-
0
0
0
1
-
5
4
0
4-0
4
1
X
TES (6 eq)
TFA, rt
Lucia Chiummiento*
0
0
0
0
-
0
0
0
1
-
8
1
8
1
-
9
1
3
8
R3
R1
b
O
a + b
OMe
R2
Department of Science, University of Basilicata,
Via dell’Ateneo Lucano 10, 85100 Potenza, Italy
lucia.chiummiento@unibas.it
R3
11 examples
OH
R
2 = H, aryl, halo
R3 = H, EWG, EDG
LDe.MeCpahaiCilruotlumrrcmeeiansi.ptceohnoniftuodSmicnimegniAecuent,thUoo@nriuvneirbsaitsà.itdegli Studi della Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy
Received: 09.09.2020
Accepted after revision: 30.09.2020
Published online: 22.10.2020
DOI: 10.1055/s-0040-1705949; Art ID: st-2020-d0491-l
O
R2
bibenzyl
O
R1
OH
Abstract Various polysubstituted benzofurans were reduced by using
triethylsilane in trifluoracetic acid. 2,3-Dihydrobenzofurans or bibenzyl
compounds were obtained in high yields, depending on the nature of
the substituents at C2 and on the benzene ring of the core structure. A
p-anisole substituent at C2 of benzofurans always led to the corre-
sponding bibenzyls.
stilbenes
radstrictin H
DHBF
OH
BF
OMe
OH
OH
OH
O
O
MeO
OMe
OMe
moracin A
licarin A
Key words benzofurans, dihydrobenzofurans, bibenzyls, triethylsi-
lane, trifluoroacetic acid, reduction
Figure 1 Examples of natural stilbenoids
2,3-Dihydrobenzofuran-based compounds as well as
derivatives of bibenzyl (1,2-diarylethanes) are found in a
range of natural products. Stilbenoids and benzofurans
have become of particular interest for their various biologi-
cal and pharmacological activities (Figure 1). 2,3-Dihydro-
benzofurans exhibit antiviral, antibacterial, antiinflamma-
tory, antiangiogenic, and antimitotic activities,1 whereas
bibenzyls show other biological and agrochemical activi-
ties,2 and are also used as starting materials for the synthe-
sis of drug molecules.3 This has triggered substantial re-
search efforts into the development of efficient methods for
the preparation of dihydrobenzofurans, both in racemic
and enantioenriched forms,4 and for a more direct prepara-
tion of bibenzyls.
The hydrogenation of benzofurans represents, in princi-
ple, the most direct and most straightforward approach to
2,3-dihydrobenzofurans, but it is widely considered as un-
attractive, and few examples have been described.5 The cat-
alytic hydrogenation of benzofuran under harsh reaction
conditions is often accompanied by partial cleavage of the
furan ring and the formation of 2-ethylcyclohexanol and 2-
cyclohexylethanol, thereby restricting its practical applica-
tion. However, reductive methods have been used for the
preparation of symmetric and nonasymmetric bibenzyl de-
rivatives in good yields.6
In the last decade, reports have been published on
asymmetric hydrogenations under medium to high pres-
sures of hydrogen by using various catalytic systems, for ex-
ample, Ru,7 Rh,8 or Ir9 complexes.
Catalytic hydrogenation was used in the synthesis of
(±)-ampelopsin B and (±)--viniferin.10 Either Pd-catalyzed
hydrogenation or a combination of NH4 and Mg in metha-
nol has been used on a range of 2-aryl-3-(alkoxycarbon-
yl)benzofurans, affording cis- or trans-2,3-dihydrobenzofu-
rans, respectively.1c However, all such methods for the di-
rect reduction of variously substituted benzofurans appear
to be substrate-dependent and, consequently, developing a
general and selective reductive method to access 2,3-dihyd-
robenzofurans remains a challenge.
In line with our interest in designing suitable benzofu-
rans11 and 2,3-dihydrobenzofurans12 for the synthesis of
natural products, we report the direct reduction of various
substituted benzofurans by using a triethylsilane/trifluoro-
acetic acid (TES/TFA) system, in an attempt to understand
how substituents affect the reduction of benzofurans.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
R. D’Orsi et al.
Letter
Synlett
There has been only one report on the reduction of 2,3-
diarylbenzofurans by using TES/TFA,13 whereas several ex-
amples of reductions of 2,3-dialkylbenzofurans have been
described.14
gave the 2,3-dihydrobenzofuran 2h, whereas methyl 2-(4-
methoxyphenyl)-1-benzofuran-5-carboxylate (1i), with an
electron-donating group on the 2-aryl substituent, gave the
over-reduction product 3i. The presence of a weakly induc-
tively electron-withdrawing para-chloro group on the 2-
aryl substituent made substrate 1j reactive toward reduc-
tion, with over-reduction occurring after an extended reac-
tion time. Switching to a para-trifluoromethyl group on the
2-aryl substituent in 1k, where the trifluoromethyl group
decreased the electron-releasing effect of the oxygen, re-
sulted in slow reduction to give 2k. Benzofuran 1l, with an
electron-withdrawing group at C5 and an electron-donat-
ing para-methoxy group on the 2-aryl substituent, under-
went slow over-reduction to product 3l, without any trace
of the corresponding dihydrobenzofuran 2l. Compound 1m,
with a para-acetoxy group on the 2-aryl substituent, gave
the deacetylated derivative 1m′ as the sole product, and no
reduced product was observed, despite the electron-donat-
ing nature of the hydroxy group. This suggested a probable
transesterification reaction leading to an intermediate tri-
fluoroacetoxy derivative that was incapable of being re-
duced and underwent subsequent hydrolysis on workup.
Benzofuran 1n bearing an electron-withdrawing group on
C5 and a 3,5-dimethoxyphenyl group on C2 proved unreac-
tive under the reduction conditions.
A series of 2-aryl (or 2-alkyl) 5-substituted benzofurans
were prepared from the parent p-substituted o-halophe-
nols and terminal alkynes by Pd-catalyzed cyclization.15
Our initial investigations on the conversion of benzofurans
into 2,3-dihydrobenzofurans were carried out by using 2-
phenyl-1-benzofuran (1a) and 2-hexyl-1-benzofuran 1b
(Scheme 1). The reaction of 1a (0.5 mmol) with TES (3
mmol) in TFA (7.5 mL) at room temperature for 18 hours led
to the ring-opened product 3a without any trace of 2-phe-
nyl-2,3-dihydro-1-benzofuran (2a),16 whereas the same re-
action on 1b (0.5 mmol) with TES (3 mmol) in TFA (7.5 mL)
at room temperature for six hours led to 2-hexyl-2,3-dihy-
dro-1-benzofuran (2b) exclusively, with 60% conversion.
The reaction was then performed on some 2,5-disubstitut-
ed benzofurans. 2-Phenyl-1-benzofurans 1c–e, bearing an
electron-withdrawing group at C5, reacted slowly (with
conversions of up to 42%) and gave dihydrobenzofurans 2c–
e exclusively. The formyl group in compound 1f was not tol-
erated, leading to the formation of many degradation prod-
ucts.
Reduction of 5-hydroxy-2-phenyl-1-benzofuran (1g)
led to the ring-opened product 3g exclusively. Compound
1h, bearing an alkyl substituent at C2, as in compound 1b,
As 1j and 1k afforded the best reductive outcome to
produce 2,3-dihydrobenzofurans, various 5-methoxycar-
R2
R2
R2
R1
TES (6 eq)
TFA, rt
+
R1
R1
O
O
OH
1
2
3
R1 = hexyl, Ph, 4-MeOC6H4, 4-ClC6H4, 4-F3COC6H4, 4-AcOC6H4, 3,5-(MeO)2C6H4
R2 = H, NO2, CN, CO2Me, CHO
H
O2N
NC
MeO2C
OHC
H
C6H13
O
O
O
O
O
OH
100% 3a
60% 2b
10% 2c
20% 2d
42% (30%)a 2e
1f ndb mixture
OMe
MeO2C
HO
MeO2C
MeO2C
MeO2C
MeO2C
Cl
Cl
C6H13
OCF3
OCF3
O
O
100% (90%)a 2h
O
OH
OH
2j
2k
100% 3g
100% 3i
MeO2C
3j
OH
OMe
3k
OH
OMe
OMe
O2N
OH
95% (69%)a 2j/3j 74:26
NC
NC
80%c (58%)a 2k/3k 63:37
O
O
OH
40%d 1m
100% 1n
100% 3l
deprotected
Scheme 1 Reduction of 2-substituted and 2,5-disubstituted benzofurans. Reagents and conditions: 1 (1 mmol), Et3SiH (6.0 equiv), TFA (0.5 mL), rt, 2–
24 h. Conversions and products ratios were determined by 1H NMR spectroscopy. a Isolated yield of the main product. b Not determined; degradation
occurred. c After 24 h, the mixture was warmed to 40 °C. d Deprotected: the phenol was recovered due to hydrolysis of the acetate group.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

C
R. D’Orsi et al.
Letter
Synlett
bonyl 2,3-disubstituted benzofurans were investigated
(Scheme 2). Compounds 4a and 4b, obtained by halogena-
tion of compounds 1j and 1k with N-bromosuccinimide or
N-iodosuccinimide, respectively, were subjected to Suzuki
cross-coupling to give compounds 5a–d.11a 3-Halogenated,
as well as 3-aryl-substituted, derivatives were tested in the
reduction reaction. In the case of the 3-iodo and 3-bromo
derivatives 4a and 4b, dehalogenation occurred first, lead-
ing to 1j as the major product, with traces of the corre-
sponding reduced products 2j and 3j. It is worth noting that
when the 3-position is substituted, as in compounds 5a–c,
reduction does not readily occur and, if it does occur, the
substitution of the 2-aryl group is critical. With a para-methoxy
substituent on the 2-aryl group, reduction occurred slowly, and
R2
R2
R2
Ar
I
Pd(PPh3)2Cl2
ArB(OH)2
NIS
R1
R1
R1
K2CO3
DMF/H2O
CH3CN
O
O
O
R
R
R
8
9
10
R = H, OMe, CO2Me, Br
1 = hexyl, Ar
2 = OH, OMe, OiPr, OAc,
OCOEt, OTBS, CO2Me
R = H, OMe, CO2Me, Br
R1 = hexyl, Ar
2 = OH, OMe, OAc, CO2Me
R
R
R
Scheme 3 Synthesis of 6-substituted 2,3-diaryl-4-alkoxy-1-benzofurans
Compounds 8, 9, and 10 were then subjected to the re-
duction conditions (Scheme 4). Compound 8a [R = CO2Me;
R1 = (CH2)5Me; R2 = OMe] gave the 2,3-dihydrobenzofuran
11a exclusively (in line with the previously examined sub-
strates 1b and 1h; Scheme 1). In this case, the reaction ap-
peared to be driven by the substituent on C2. On switching
to substrates bearing an aryl ring at C2, a somewhat puz-
zling behavior occurred. Phenyl-substituted 8b and p-(tri-
fluoromethyl)phenyl-substituted 8c did not undergo any
reduction at all, whereas 8d, containing a 3,5-dimethoxy-
phenyl group at C2, gave the corresponding 2,3-dihydro-
benzofuran 11d as the main product, and as the sole prod-
uct on quenching the reaction at low temperature. With the
aim of investigating the effect of an electron-releasing aryl
group at C2, we tested a range of para-methoxyphenyl de-
rivatives 8e–h. In all cases, over-reduction occurred and the
2,3-dihydrobenzofurans 11e–h were not obtained. In the
case of the 4-acetoxy derivative 8f, the conversion was low,
and deesterification occurred. The ester moiety at C6 did
not affect the reduction. In fact, when hydrogen (in 8g) or
bromine (in 8h) were present, over-reduction products
were also obtained. The open-chain product 12i was also
obtained when a methoxy group at C6 and an ester group at
C4 were present in benzofuran 8i.
This type of behavior was confirmed to occur generally
with 2,3-disubstituted derivatives. In the cases of the 3-
iodo derivative 9j or the 3-aryl derivatives 10k and 10l,
over-reduction occurred exclusively, although protonation
should have been more difficult. In the case of 10k, which
bore a free hydroxy group at C4, a low conversion was ob-
tained and the over-reduction product 12k was obtained.
Notably, for the two structural isomers 10l and 10m, in
which the two substituents at C4 and C6 were reversed, the
trend of reduction was different. Compound 10l furnished
the over-reduced product 12l, whereas compound 10m
gave the 2,3-dihydrobenzofuran 11m, albeit in modest
yield, confirming a report in the literature.13
the main product was the open-chain derivative 7d
.
X
MeO2C
TES (6 eq)
MeO2C
Cl
Cl
O
TFA, rt
O
4a: X = Br
4b: X = I
100% conv.
1j
R
MeO2C
TES (6 eq)
TFA, rt
no reaction
X
O
5a: X = Cl;
5b: X = Cl;
R = H
R = 3,5-(MeO)2
5c: X = OCF3; R = 3,5-(MeO)2
MeO
OMe
MeO2C
MeO
OMe
OMe
O
6d (19)
OMe
TES (6 eq)
MeO2C
MeO
TFA, rt
OMe
O
26% conv.b
OMe
5d
MeO2C
OH
7d (81)
Scheme 2 Reduction of 5-methoxycarbonyl 2,3-disubstituted benzo-
furans. Reagents and conditions: 4 or 5 (1 mmol), Et3SiH (6.0 equiv), TFA
(0.5 mL), rt, 2–24 h. Conversions and products ratios were estimated by
GC/MS.
Subsequently, C4- and/or C6-substituted 2-aryl and 2,3-
diarylbenzofurans were studied. Starting from compounds
8, in which R2 at C4 was a free hydroxy group or one pro-
tected as a methyl ether or methyl ester (8a–h)11a or as an
ester functionality (8i),17 the iodinated compounds 9 and
the corresponding 2,3-diaryl-substituted benzofurans 10
were obtained by subsequent iodination and Suzuki cross-
coupling reactions, respectively (Scheme 3).
Surprisingly, different protections of a hydroxy group at
C4 affected the reduction (Scheme 5). The isopropyl group
in 10n was removed sufficiently fast to permit subsequent
reduction (and over-reduction), affording 12k in 25% yield
after 24 hours, whereas acetyl- (10o), propionyl- (10p), or
tert-butyl(dimethyl)silyl (10q)-protected derivatives were
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

D
R. D’Orsi et al.
Letter
Synlett
R2
R2
R3
R3
R2
R3
R1
TES (6 eq)
+
R1
R1
O
TFA, rt, 24 h
O
R
R
R
OH
8a–i, 9j, 10k–m
11a–m
12a–m
R = H, OMe, CO2Me, Br
R
R
R
1 = hexyl, Ar
2 = OH, OMe, OiPr, OAc, OC(O)Et, OTBS, CO2Me
3 = H, I, 3,5-(MeO)2C6H3
OMe
OMe
OMe
OMe
OMe
OMe
C6H13
OCF3
O
O
O
O
100% a,b 11d
MeO2C
MeO2C
MeO2C
MeO2C
100%a 11a
100% 8b
100% 8c
OMe
OMe
H
OMe
OMe
OMe
OH
OAc
OMe
OMe
CO2Me
MeO2C
MeO2C
Br
MeO
OH
100% 12e
OH
OH
OH
OH
33% 12f
100% 12g
100% 12h
100% 12i
MeO
MeO
OMe
MeO
OH
OMe
OMe
OMe
OMe
OMe
MeO2C
OMe
I
OMe
OMe
O
MeO
MeO2C
OH
MeO2C
OH
100% 12l
MeO2C
OH
50% 12k
100% 12j
30% 11mc
Scheme 4 Reduction of 2,3,4,6-tetrasubstituted benzofurans. a Isolated yield of the main product. b 12d was obtained after quenching and purification
on silica gel. c A single diastereoisomer was obtained.
unreactive toward reduction, and only deprotection oc-
curred, slowly giving rise to compound 10k.
tional stabilization of the benzyl carbocation [Ar = Ph, 4-
ClC6H4, 4-F3COC6H4, 3,5-(MeO)2C6H3]. Equally, over-reduc-
tion occurs if an electron-donating group is present at the
para-position of the 2-aryl substituent. Otherwise, if an
electron-donating group is present at C5, further protona-
tion is possible and the furan ring is opened. Other substit-
uents at C5 do not affect the pattern of reduction. The reac-
tion trend is directed solely by the pattern of substitution
on the 2-aryl substituent.
Surprisingly, the formation of 2,3-dihydrobenzofurans
occurred when a carboxy group was present at C4 of the
2,3-diaryl-substituted benzofuran 10m, but no reduced
products were observed when a hydroxy group at the same
position was protected with a sterically hindered group
(10o–q). Further investigations will be carried in an at-
tempt to understand these outcomes. A probable acid–base
Lewis-type interaction occurs between the C3 aryl substit-
uent and the substituent at C4, which prevents protonation
of the furan ring and subsequent reduction and/or over-re-
duction of the benzofuran. This might be an efficient meth-
od for obtaining asymmetric bibenzyls (the over-reduced
products), which are useful as building blocks and are con-
stituents of important classes of biological compounds.
We concluded that, under these conditions of hydroge-
nation,18 when an alkyl group was present at C2 reduction
occurred and the corresponding 2,3-dihydrobenzofuran
was obtained, regardless of the substituents on the benzene
ring. However, when an aryl group was present at C2, 2,3-
dihydrobenzofurans or bibenzyls were obtained, depending
on the nature and the position of substituents on the aryl
group and on the benzofuran core.
A plausible mechanism for this reaction, depicted in
Scheme 6, explains the results in terms of the relative sta-
bilities of the intermediates that are formed. A 2-aryl sub-
stituent stabilizes the benzyl carbenium ion formed under
acidic conditions by furyl ring opening, so that over-reduc-
tion can occur provided no substituent on the benzene ring
slows down the over-reduction (as in the case of R = H). The
mesomeric effect of substituents of the 2-aryl substituent
influences the stabilization of the benzylic carbocation.
Moreover, an electron-withdrawing group at the 5-position
of the benzofuran ring (R = CN, NO2, CO2Me) favors the for-
mation of 2,3-dihydrobenzofurans in the absence of addi-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

E
R. D’Orsi et al.
Letter
Synlett
Funding Information
MeO
OH
OMe
We would like to thank the University of Basilicata for financial sup-
port.
U
n
i
versiàt
d
e
gl
i
Studi
d
elaBasilicata()
OMe
MeO
OiPr
O
MeO2C
OMe
Supporting Information
55%
10k
TES/TFA
MeO
OH
OMe
Supporting information for this article is available online at
OMe
24 h
https://doi.org/10.1055/s-0040-1705949. Su
p
p
ortingInformatio
n
Su
p
p
ortingInformatio
n
OMe
O
10n
MeO2C
References and Notes
MeO2C
OH
MeO
OAc
25%
12k
(1) (a) Keylor, M. H.; Matsuura, B. S.; Stephenson, R. J. Chem. Rev.
2015, 115, 8976. (b) Chen, K.; Pitchakuntla, M.; Jia, Y. Nat. Prod.
Rep. 2019, 36, 666. (c) Qin, L.; Vo, D.-D.; Nakhai, A.; Andersson,
C. D.; Elofsson, M. ACS Comb. Sci. 2017, 19, 370. (d) Ghosh, A. K.;
Cheng, Z.; Zhou, B. Org. Lett. 2012, 14, 5046.
(2) (a) Asakawa, Y.; Nagashima, F.; Ludwiczuk, A. J. Nat. Prod. 2020,
83, 756. (b) Zhang, C.-Y.; Gao, Y.; Zhu, R.-X.; Qiao, Y.-N.; Zhou, J.-
C.; Zhang, J.-Z.; Li, Y.; Li, S.-W.; Fan, S.-H.; Lou, H.-X. J. Nat. Prod.
2019, 82, 1741. (c) Zhou, X.-M.; Zheng, C.-J.; Gan, L.-S.; Chen, X.-
P.; Zhang, G.-Y.; Song, X.-P.; Li, G.-N.; Sun, C.-G. J. Nat. Prod
2016, 79, 1791.
OMe
OMe
O
10o
TES/TFA
24 h
MeO2C
quant.
MeO
MeO
OH
O
OMe
OMe
TES/TFA
48 h
Et
O
(3) (a) Hofer, A.; Kovacs, G.; Zappatini, A.; Leuenberger, M.;
Hediger, M. A.; Lochner, M. Bioorg. Med. Chem. 2013, 21, 3202.
(b) Wyatt, P.; Hudson, A. Org. Biomol. Chem. 2004, 2, 1528.
(4) For recent advances in the synthesis of 2,3-dihydrobenzofurans,
see: Laurita, T.; D’Orsi, R.; Chiummiento, L.; Funicello, M.;
Lupattelli, P. Synthesis 2020, 52, 1451.
(5) Bertolini, F.; Pineschi, M. Org. Prep. Proced. Int. 2009, 41, 385.
(6) (a) Vontzalidou, A.; Zoidis, G.; Chaita, E.; Makropoulou, M.;
Aligiannis, N.; Lambrinidis, G.; Mikros, E.; Skaltsounis, A.-L.
Bioorg. Med. Chem. Lett. 2012, 22, 5523. (b) Liu, J.; Li, B. Synth.
Commun. 2007, 37, 3273. (c) Xiao, Z.-P.; Ma, T.-W.; Fu, W.-C.;
Peng, X.-C.; Zhang, A.-H.; Zhu, H.-L. Eur. J. Med. Chem. 2010, 45,
5064.
quant.
OMe
OMe
O
MeO2C
O
MeO2C
10p
10k
MeO
TES/TFA
24 h
OMe
OTBS
50%
OMe
O
MeO2C
10q
Scheme 5 Reduction of benzofurans 10n–q
(7) (a) Ortega, N.; Urban, S.; Beiring, B.; Glorius, F. Angew. Chem. Int.
Ed. 2012, 51, 1710. (b) Ortega, N.; Beiring, B.; Urban, S.; Glorius,
F. Tetrahedron 2012, 68, 5185.
(8) Yamashita, M.; Negoro, N.; Yasuma, T.; Yamano, T. Bull. Chem.
Soc. Jpn. 2014, 87, 539.
R
R
R
Ar
TES (6 eq)
TFA, rt
Ar
Ar
+
O
O
OH
1
2
3
CF3COOH
H+
H
H
H
R
R
R
R
Et3SiH
Ar
+
Ar
Ar
Ar
Ar
O+
H
O
O
O
H-
2
CF3COOH
H
H
H
H
R
R
Ar
R
R
Ar
Et3SiH
Ar
+
H
H
H
H–
H
H
O+
OH
O
O
3
H
H+
H
extra stabilization
of benzyl cation
Scheme 6 Possible mechanism of reduction to 2,3-dihydrobenzofurans and 1,2-diarylethanes
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

F
R. D’Orsi et al.
Letter
Synlett
(9) Pauli, L.; Tannert, R.; Scheil, R.; Pfaltz, A. Chem. Eur. J. 2015, 21,
1482.
(10) Lindgren, A. E. G.; Öberg, C. T.; Hillgren, J. M.; Elofsson, M. Eur. J.
Org. Chem. 2016, 426.
(16) Several trials were performed by changing the amount of TES
(1–12 equiv), the solvent (CH2Cl2, toluene, AcOH, or TFA), the
reducing agent (NaBH4 or TES), and the temperature (0–40 °C),
without any meaningful improvement in the conversion or the
ratio of reduced products.
(17) Benzofuran 8i was prepared according to the reported proce-
dure; see: Liu, J.-t.; Do, T. J.; Simmons, C. J.; Lynch, J. C.; Gu, W.;
Ma, Z.-X.; Xu, W.; Tang, W. Org. Biomol. Chem. 2016, 14, 8927.
(18) TFA/TES Reduction: Typical Procedure
(11) (a) Chiummiento, L.; Funicello, M.; Lopardo, M. T.; Lupattelli, P.;
Choppin, S.; Colobert, F. Eur. J. Org. Chem. 2012, 188.
(b) Convertini, P.; Tramutola, F.; Iacobazzi, V.; Lupattelli, P.;
Chiummiento, L.; Infantino, V. Chem.-Biol. Interact. 2015, 237, 1.
(12) Laurita, T.; Chiummiento, L.; Funicello, M.; D’Orsi, R.; Sallemi,
D.; Tofani, D.; Lupattelli, P. Eur. J. Org. Chem. 2019, 4397.
(13) (a) Zhang, J.; Kang, Y.; Shi, J.; Yao, C. Synlett 2016, 27, 1587.
(b) Romero, K. J.; Keylor, M. H.; Griesser, M.; Zhu, X.; Strobel, E.
J.; Pratt, D. A.; Stephenson, C. R. J. J. Am. Chem. Soc. 2020, 142,
6499.
(14) Lau, C. K.; Bélanger, P. C.; Dufresne, C.; Scheigetz, J.; Therien, M.;
Fitzsimmons, B.; Young, R. N.; Ford-Hutchinson, A. W.;
Riendeau, D.; Denis, D.; Guay, J.; Charleson, S.; Piechuta, H.;
McFarlane, C. S.; Chiu, S.-H. L.; Chiu, D.; Eline, R. F.; Alvaro, G.;
Miwa, J.; Walsh, L. J. Med. Chem. 1992, 35, 1299.
In a round-bottomed flask under an Ar atmosphere, the appro-
priate benzofuran substrate (0.5 mmol) was dissolved in TFA
(7.5 mL), and TES (6 equiv) was added. The reaction was moni-
tored every hour by GC/MS. When complete, the reaction was
quenched with aq NaHCO3 at 0 °C until the effervescence
stopped. The mixture was then extracted with EtOAc (×3), and
the extracts were washed with brine, dried (Na2SO4), filtered,
and concentrated under vacuum. The crude product was ana-
lyzed by GC/MS or NMR. Generally, the dihydrobenzofurans had
similar Rf values to those of the starting benzofurans, so purifi-
cation by column chromatography on silica gel was avoided
when the reaction showed a low conversion.
(15) (a) Heravi, M. M.; Sadjadi, S. Tetrahedron 2009, 65, 7761.
(b) Bochicchio, A.; Chiummiento, L.; Funicello, M.; Lopardo, M.
T.; Lupattelli, P. Tetrahedron Lett. 2010, 51, 2824.
(c) Chiummiento, L.; D’Orsi, R.; Lupattelli, P. Molecules 2020, 25,
2327.
2-Hexyl-2,3-dihydro-1-benzofuran (2b)
Prepared by reduction of 1b with according to the typical pro-
cedure; yield: 60% (NMR). 1H NMR (500 MHz, CDCl3);  = 7.56s
(s, 1 H), 7.12 (m, 2 H), 6.81 (m, 1 H), 4.75 (m, 1 H), 3.25 (m, 2 H),
2.85 (m, 2 H), 1.25 (m, 8 H), 0.81 (m, 3 H).
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F